Traumatic or ischemic brain, spinal cord and peripheral nervous system injuries involve serious physical (hemiplegia, paraplegia, quadriplegia), sensory (neuropathic pain, numbness, loss of vision) or cognitive (mental changes) consequences for the patient. They are a public health problem as these handicaps generate a loss of autonomy and total dependence requiring heavy medical care throughout life. For example, the economic consequences of a spinal cord injury, including medical and para-medical, home health aides, housing and vehicles changes as well as lost productivity have been estimated to be nearly $10 billion per year in the United States of America (USA). In addition, compression of peripheral nerves by disc herniation causes chronic pain. In the USA, low back pain (also called lumbago) is the fifth most common reason for physician visits. About nine out of ten adults experience back pain at some point in their life, and five out of ten working adults have back pain every year. Low back pain causes 40% of missed days of work in the USA. Also, it is the leading cause of disability worldwide. Herniated disc causing compression of a peripheral nerve is the most common neurologic impairment associated with this condition of low back pain.
Spasticity, characterized by hyperexcitability of the stretch reflex, muscle stiffness, co-contraction of antagonistic muscles and painful spasms, is a common consequence of spinal cord injury (SCI, 75% of patients) or cerebrovascular accident (CVA or stroke). Associated (in the case of SCI) or not (in the case of stroke) with neuropathic pain, it deeply affects the quality of life of patients.
Baclofen is commonly used for treating severe spasticity and can be administered in a patient by means of an implanted pump when the oral administration either becomes inefficient or has too many side effects (such as drowsiness, dizziness . . . ). However, treatments using baclofen are very expensive, even without counting the surgery act for implantation of the pump.
Other drugs such as morphine, gabapentine, pregabaline (Lyrica), clonazepam, diazepam (Valium), and/or ketamin can also be used for treating neuropathic pain and/or spasticity but generally trigger, several side effects as dependency issues. Botulinum toxin (Botox®) intramuscular injection has also showed an effect for treating spasticity in an isolated muscle while provoking weakness of the injected muscle as side effect, which could spread towards neighboring muscles.
As discussed above, no patient's medication is likely to deal effectively and on long-term basis with spasticity while avoiding side effects so that novel therapeutic approaches, drugs, and/or treatments have to be investigated.
Spasticity results from both an increase of excitability of motor neurons and a reduction of the strength of the inhibition in the neural network of the spinal cord. The mechanism responsible for the alteration of neuronal inhibition has recently been identified. The inhibitory action is based on a low chloride ion concentration in target cells (Payne et al., 2003; Vinay, 2008). This low concentration is regulated by proteins specifically expressed in the membrane of neurons, the potassium chloride cotransporter 2 (KCC2), expelling potassium and chloride ions outside cells. The KCC2 expression is greatly decreased after spinal cord injury (Boulenguez et al., 2010). A similar reduction in the amount of KCC2 transporters is also responsible for neuropathic pain after spinal cord injury (Lu et al., 2008; Cramer et al., 2008) or peripheral nerve ligation (Coull et al., 2003; Coull et al., 2005).
Accordingly, KCC2 appears to be an attractive target for treating spasticity or chronic pain but, up to now, no drug or pharmacological tools having a positive activity on KCC2 by increasing expression or functions thereof has been developed yet.